Monoclonal gammopathy of uncertain significance (MGUS) is a common, pre-malignant plasma cell disorder found in 3.2 and 5.3 percent of individuals over the ages of 50 and 70 years respectively (Kyle RA, NEJM, 2006). MGUS is characterized by monoclonal serum immunoglobulin, an increased risk of thrombosis, an increased risk of osteoporosis and bone fractures and a risk of developing malignancy (predominantly multiple myeloma at 1% per year (REFS Kyle RA, NEJM, 2002). MGUS has a significant component of inherited risk, and is found at 2-3 fold higher rates in African Americans, and 2-fold higher rates in family members of MGUS patients. Neither the genetic basis nor the environmental factors contributing to MGUS/MM risk have been defined. Our long-term goal is to develop screening and prevention strategies based on a detailed understanding of MGUS/MM genetics. The C57BL/KaLwRij (KaLwRij) mouse strain, described decades ago (Radl J, Clin Exp Immunol, 1984), develops MGUS at high frequency with many of the same features of the human disease including an increased risk of developing MM. Since the most common somatic mutations to occur in MGUS/MM are chromosomal translocations involving immunoglobulin heavy chain switch regions, our hypothesis is that germline susceptibility to MGUS is the consequence of abnormal immunoglobulin isotype switching. We found highly significant differences in antibody isotype responses by ELISA between KaLwRij and 11 separate mouse strains. We also found that ionizing radiation and vitamin D deprivation, two environmental factors associated with MM, induced significant and strain-specific changes in antibody responses in mice. To advance our understanding of MGUS/MM risks, we propose: Specific Aim 1: Characterize effects of ionizing radiation, vitamin D deprivation and strain background on immunoglobulin isotype responses and monoclonal gammopathy (MGUS) development in mice; Specific Aim 2: Map quantitative trait loci (QTL) for MGUS/MM risk and identify somatic mutations associated with disease progression. The experiments in SA1 will provide valuable insights into the effects of strain and relevant environmental factors to MGUS development. The experiments in SA2 will provide an MGUS-specific QT data set and matched DNA samples that will allow us to identify QTL's in mice associated with MGUS risk. These mice will be used as a platform to explore the relationship between inherited MGUS risk and environmental factors and the data we generate will inform ongoing genome-wide association (GWA) studies in humans (a collaborative effort between Washington University and the Mayo Clinic). This project will be part of a coordinated effort to identify the genetic factors that drive MGUS and MM in humans.